The proposed research deals with the origin and migration of thymic lymphocytes, and with the mechanism of immunological tolerance. The hypothesis that has gained wide acceptance is that thymic lymphocytes are derived from invading hemocytoblast-like cells rather than from the thymus rudiment itself. However, studies in my laboratory have revealed that, at least in amphibians, thymic lymphocytes are ontogenetically derived from elements of the thymic primordium rather than from blood-borne stem cells that migrated into the developing organ. The proposed program is aimed at reinforcing the view that there are indigenous stem cells in the thymus and, moreover, that circulating cells, presumably derived from the bone marrow, do not continuously migrate into the thymus in later life. In other words, lymphopoiesis in the thymus of the frog is genuinely self-sustaining. In recent years, the classic interpretation of tolerance has been challenged. The classic view, based on Burnet's clonal selection theory, is that tolerance is the consequence of the deletion of the clone of lymphocytes of relevant specificities. Results of recent studies suggest that tolerant animals do contain immunologically competent lymphocytes which are prevented from attacking what would otherwise be their target by the interposition of a serum factor. Amphibians provide a favorable experimental model to examine the possibility of a serum blocking effect.